Method for preparing an optically pure benzofuran carboxylic acid and use thereof for preparing efaroxan

ABSTRACT

A method for preparing an optically pure 2-ethyl-2,3-dihydrobenzofurancarboxylic acid of formula II wherein R is a hydrogen atom, halogen, lower alkyl, lower alkoxy or hydroxy is described. ##STR1## The method comprises separating the racemic mixture by selective crystallization with the suitable optically pure enantiomer of 2-phenylglycinol, in a suitable solvent, whereafter the optically pure, crystallized acid of formula II is isolated and recovered. The invention also provides the optically pure 2-ethyl-2,3-dihydro-benzofurancarboxylic acid derivative thus obtained and the use thereof for the preparation of an optically pure derivative of efaroxan.

This application is a 371 of PCT/FR96/00697 filed May 9, 1996.

The present invention relates to a process for the preparation of anoptically pure 2-ethyl-2,3-dihydrobenzofurancarboxylic acid derivative,to the derivative obtained and to its use for the preparation of thecorresponding optically pure 2-2-(2-ethyl-2,3-dihydrobenzofuryl)!-2-imidazoline derivative, inparticular efaroxan.

2- 2-(2-Ethyl-2,3-dihydrobenzofuryl)!-2-imidazoline derivatives, inparticular efaroxan, are derivatives that antagonize α2-adrenergicreceptors and are described in European patent application No. 0,071,368(Reckitt & Colman) for the treatment of depression or migraine. They arealso described for the treatment of Parkinson's disease andneurodegenerative disorders, such as Alzheimer's disease, in WO patentapplications No. 95/00145 and No. 95/01791 (Pierre Fabre Medicament).

Their enantiomers are described in WO patent application No. 92/05171,(-)-efaroxan being described in particular for treating diabetes, as apotassium-channel blocker. They are obtained by racemic resolution withdibenzoyl tartaric acid, at the final stage of the synthesis.

The present invention relates to a novel process for the stereospecificsynthesis of optically pure 2-2-(2-ethyl-2,3-dihydrobenzofuryl)!-2-imidazoline derivatives of generalformula I ##STR2## in which R represents a hydrogen or halogen atom or alower alkyl, lower alkoxy or hydroxyl radical, starting with acorresponding optically pure 2-ethyl-2,3-dihydrobenzofurancarboxylicacid derivative, and to the optically pure derivatives obtained by meansof this process.

The synthesis of the derivatives of general formula I is moreparticularly described in patent application EP-A-0,071,368 and consistsin converting the corresponding 2-ethyl-2,3-dihydrobenzofurancarboxylicacid derivative into an amide of general formula III ##STR3## in which Ris defined above, and then into the corresponding cyano derivative ofgeneral formula IV, by dehydration, ##STR4## which compound is thenconverted into the derivative of general formula I, using the usualtechniques, with ethylenediamine.

The specific synthetic process according to the invention repeats thisgeneral scheme, with the corresponding optically pure2-ethyl-2,3-dihydrobenzofurancarboxylic acid derivative as startingacid.

The present invention thus relates firstly to the process for thepreparation of the starting acid of general formula II ##STR5## in whichR represents a hydrogen or halogen atom or a lower alkyl, lower alkoxyor hydroxyl radical, in which process the racemic mixture is resolved byselective crystallization with the appropriate optically pure enantiomerof 2-phenylglycinol, in a suitable solvent, after which the crystallizedoptically pure acid of formula II is recovered.

The expression "appropriate optically pure enantiomer of2-phenylglycinol" is understood to refer to the enantiomer of the acidwhich allows good separation of the diastereoisomeric salts obtained,one being more stable than the other, and which crystallizing. Thus, theacid of general formula II of R configuration is obtained by selectivecrystallization with S-(+)-2-phenylglycinol and, conversely, the acid ofS configuration is obtained with R-(-)-2-phenylglycinol.

The term "suitable solvent" is understood to refer to any solvent whichis capable of assisting the selective crystallization of an enantiomericsalt, while at the same time keeping the other in solution. It will bechosen advantageously from acetone, ethyl acetate, methyl ethyl ketoneand mixtures thereof.

The preparation of the racemic acid of general formula II is describedin the Journal of Heterocyclic Chemistry (1987, 24, 495).

The principle of selective crystallization by formation ofdiestereoisomeric salts is a known principle. However, it is difficultand hazardous to carry out, in particular when it involves obtaininghigh optical purity, that is to say greater than or equal to 95%.

One method for separating enantiomers of acids such as the acid ofgeneral formula II has been described, and does not involve selectivecrystallization of diastereoisomeric salts but esterification withoptically active menthol (Chem. Pharm. Bull., 1988, 36, 902), whichrequires an additional step of hydrolysis of the diastereoisomeric esterisolated.

Various chiral amines can be used to form a diastereoisomeric salt withthe acid of general formula II, such as, for example,α-methylbenzylamine, or amino alcohols such as optically activephenylalaninol or prolinol.

However, resolution tests on 2-ethyl-2,3-dihydrobenzofurancarboxylicacid with the enantiomers of these three alcohols was unfruitful, onlyoptically pure 2-phenylglycinol allowing a sharp separation of thediastereoisomeric salts by selective crystallization.

S-(+)-2-Phenylglycinol is an amino alcohol which is readily available byreduction of S-(+)-phenylglycine (Tetrahedron Lett., 1992, 33, 5517),and its use for separating certain racemic acids whose structure isremote from the acids of general formula II is described in particularin Japanese patent applications No. 58 029 719, No. 53 018 529 and No.03 095 138.

The results of these tests of crystallization from ethyl acetate oracetone are reported in Table I below, the purity of the saltscrystallized being verified by HPLC (column: chiral×(250×4 mm)β-cyclodextrin; eluent: 1% TEAA buffer, pH 4.1, with 15% MeOH).

                  TABLE I    ______________________________________    CHIRAL ALCOHOL                  RESULT         HPLC    ______________________________________    R-(+)-α-methylbenzyl-                  crystallization 2 salts                                 2 peaks of    amine                        equal intensity    S-(-)-phenylalaninol                  crystallization 2 salts                                 2 peaks of                                 equal intensity    S-(+)-prolinol                  no crystallization                                 --    R-(-)-2-phenylglycinol                  crystallization with                                 a single peak                  the (-) enantiomer    S-(+)-2-phenylglycinol                  crystallization with                                 a single peak                  the (-) enantiomer    ______________________________________

The present invention also relates to the optically pure derivatives ofgeneral formula II which can be obtained by the above process, inparticular derivatives having an enantiomeric purity greater than orequal to 95%, more particularly greater than 96.5%.

Starting with this optically pure acid, the corresponding derivatives ofgeneral formula I are prepared, while conserving the absoluteconfiguration of the product.

The reaction scheme for the preparation of the derivatives of generalformula I, starting with the racemic acid, is given overleaf for thepreparation of R-(+)-efaroxan, that is to say R represents a hydrogenatom.

The racemic mixture of the acid of formula II in which R=H is placed inacetone, ethyl acetate or methyl ethyl ketone in the presence of astoichiometric amount of S-(+)-phenylglycinol. After crystallization,the diastereoisomeric salt of(+)-2-ethyl-2,3-dihydrobenzofurancarboxylic acid (A+) and ofS-(+)-phenylglycinol (B+) is isolated. The other diastereoisomeric saltformed between (-)-2-ethyl-2,3-dihydrobenzofurancarboxylic acid andS-(+)-phenylglycinol remains in solution. The NMR spectrum of thespecies (A+) (B+) shows a single compound.

On passage to the free acid form in the presence of hydrochloric acid,the enantiomerically pure (+)-2-ethyl-2,3-dihydrobenzofurancarboxylicacid is obtained. This acid is converted into the ester by treatmentwith SOCl₂ /MeOH and the methyl ester obtained is then treated withaqueous ammonia in order to form the amide which, by dehydration with P₂O₅ in toluene, gives the corresponding nitrile. The final stage of thesynthesis consists in preparing the imidate from the nitrile, byreaction with a catalytic amount of sodium methoxide, which is thentreated with ethylenediamine in a solution of isopropanol andhydrochloric acid, in order to obtain the desired imidazoline.

The overall yield for the preparation of the dextrorotatory isomer of2-ethyl-2,3-dihydrobenzofuran-2-carboxylic acid is 50% starting from itsracemic mixture, and the preparation of (+)-2-2-(2-ethyl-2,3-dihydrobenzofuryl!-2-imidazoline in hydrochloride form is50%. ##STR6##

Other characteristics of the process according to the invention willbecome apparent in the light of the examples below for the selectivepreparation of R-(+)-efaroxan.

EXAMPLE 1 (+)-2-Ethyl-2,3-dihydro-2-benzofurancarboxylic acid

Racemic 2-ethyl-2,3-dihydro-2-benzofurancarboxylic acid (6 g; 31.2 mmol)is dissolved in 50 ml of ethyl acetate and mixed with a solution ofS-(+)-2-phenylglycinol (4.29 g; 31.2 mmol) in 100 ml of ethyl acetate.The crystals are filtered off and recrystallized twice from methyl ethylketone in order to give an enantiomeric purity of 96.6%; α!D=+55.9°(C=0.3; MeOH). The free acid is obtained by extraction in CH₂ Cl₂ and 1NHCl in order to give 1.52 g (50%) of crystals which are used in step 2of Example 2.

Starting with the same racemic acid but using R-(-)-2-phenylglycinol,the diastereoisomeric salt is obtained after two recrystallizations fromacetone and methyl ethyl ketone. Crystals are obtained whose opticalrotation is: α!D=-55.70° (C=0.26; MeOH).

EXAMPLE 2 Methyl (+)-2-ethyl-2,3-dihydro-2-benzofurancarboxylate

The enantiomerically pure acid obtained in Example 1 is treated with 0.5ml of SOCl₂ in 100 ml of methanol, at room temperature overnight,followed by evaporation, to give 1.5 g of methyl ester.

EXAMPLE 3 (+)-2-Ethyl-2,3-dihydro-2-benzofurancarboxamide

The ester from the above stage is placed in 50 ml of concentratedaqueous ammonia solution, with stirring at room temperature. Afterevaporation, 1.38 g of crude amide compound are obtained, which productis used in the following step.

EXAMPLE 4 (+)-2-Ethyl-2,3-dihydro-2-cyanobenzofuran

The amide of Example 3 is treated with 5 g of P₂ O₅ in 50 ml ofrefluxing toluene for 16 h. After separation of the phases by settlingand the usual extraction, 1.06 g of nitrile are obtained, which productis used directly in the following step.

EXAMPLE 5 (+)-2- 2-(2-Ethyl-2,3-dihydrobenzofuryl)!-2-imidazolinehydrochloride

The nitrile obtained in Example 4 (1 g) is placed in ethanol (50 ml) andtreated with a catalytic amount of sodium methoxide at 0° C., and thenleft at room temperature for six days. At the end of the reaction (TLC),0.582 ml of ethylenediamine is added to the reaction medium, followed bya 5 N solution of isopropanol saturated with hydrogen chloride gas. Thereaction mixture is stirred for four days and is then extracted with CH₂Cl₂ and 1 N sodium hydroxide solution, and 702 mg of the compound inbase form are thus obtained, the hydrochloride of which is formed inether by addition of 0.62 ml of isopropanol HCl (5 N). Recrystallizationfrom acetonitrile gives the hydrochloride in the form of pure crystals.

m.p.=246° C.; α!D sic!=+99.32 (C=0.29; MeOH) IR (KBr): ν cm⁻¹ =2977,2901, 1603, 1480, 1460 ¹ H-NMR (DMSO): δ=0.90 (t, 3H, J=7.2 Hz, CH₃);1.95-2.2 (m, 2H, CH₂ ethyl); 3.35 (d, 1H, J=16.7 Hz, ArCH_(A)); 3.57(d=1H, J=16.7 Hz, ArCH_(B)); 3.85 (s, 4H, 2CH₂ imidazoline); 6.86-6.95(m, 2H, H₅ -H₇); 7.13-7.25 (m, 2H, H₄ -H₆) ; 9.20 (d, 1H, NH).

Enantiomeric purity: 99.9%

Tests of separation of the racemic acids II having a substituent R=4-Fand R=5-F lead to the production of the corresponding, optically pure,dextrorotatory acids II. These acids are used to prepare thecorresponding, enantiomerically pure compounds derived from generalformula I, which also form part of the present invention:

(+)-2- 2-(2-ethyl-4-fluoro-2,3-dihydrobenzofuryl)!-2-imidazolinehydrochloride;

(+)-2- 2-(2-ethyl-5-fluoro-2,3-dihydrobenzofuryl)!-2-imidazolinehydrochloride.

We claim:
 1. Process for the preparation of an optically pure2-ethyl-2,3-dihydrobenzofurancarboxylic acid derivative of formula II##STR7## in which R represents a hydrogen or halogen atom or a loweralkyl, lower alkoxy or hydroxyl radical, in which process the racemicmixture is resolved by selective crystallization with the appropriateoptically pure enantiomer of 2-phenylglycinol, in a suitable solvent,after which the crystallized optically pure acid of formula II isrecovered.
 2. Process according to claim 1, wherein the acid of formulaII of R-(+) configuration is obtained by selective crystallization withS-(+)-2-phenylglycinol.
 3. Process according to claim 1 wherein thesolvent is selected from acetone, ethyl acetate, methyl ethyl ketone andmixtures thereof.
 4. Optically pure2-ethyl-2,3-dihydrobenzofurancarboxylic acid of formula II which can beobtained by the process according to claim
 1. 5. Optically pure2-ethyl-2,3-dihydrobenzofurancarboxylic acid of formula II, ##STR8## 6.Optically pure R-(+)-2-ethyl-2,3-dihydrobenzofurancarboxylic acidaccording to either of claim
 5. 7. Process for the preparation of anoptically pure 2- 2-(2-ethyl-2,3-dihydrobenzofuryl)!-2-imidazolinederivative of formula I ##STR9## in which R represents a hydrogen orhalogen atom or a lower alkyl, lower alkoxy or hydroxyl radical, byconversion of the optically pure 2-ethyl-2,3-dihydrobenzofurancarboxylicacid derivative of corresponding formula II, defined according to one ofclaim
 4. 8. Process according to claim 7, characterized in that the 2-2-(2-ethyl-2,3-dihydrobenzofuryl)!-2-imidazoline derivative of formula Iand the corresponding optically pure2-ethyl-2,3-dihydrobenzofurancarboxylic acid of formula II are each of Rconfiguration.
 9. Process according to claim 8, characterized in that Rrepresents a hydrogen atom and the 2-2-(2-ethyl-2,3-dihydrobenzofuryl)!-2-imidazoline derivative of formula Iand the corresponding optically pure2-ethyl-2,3-dihydrobenzofurancarboxylic acid of formula II are each of Rconfiguration and dextrorotatory (+).